The Role of CPG15 in the Development of Nervous System.

Abstract

The vertebrate brain is a highly organized, complex structure which processes information it receives through the sensory organs. The brain consists of more specialized cell types than found in the rest of the body combined. These cells including neurons and glia, are organized to form an intricate circuitry that has been evolutionarily optimized for information processing resulting in the survival of these animal species. Neurons are unique cells in that they are intrinsically excitable and can release chemical neurotransmitters in response to electrical signals. These properties enable them to communicate with one another rapidly, on the orders of one thousandth of a second, allowing them to process information. Morphologically, neurons are asymmetrical cells whose polarity is essential for their function. In general, they receive information from up to thousands of other cells in the form of neurotransmitters released onto their elaborate dendritic processes. The information is processed according to the type of neuron and converted to the output of the cell in the form of action potential, an electrical activity set by gradients of positive and negative ions across the plasma membrane. The action potential travels from its site of generation at the axon hillock down the axon, a long process that connects to many other cells. This results in the release of neurotransmitter at the axon terminal further propagating the information to target cells. Understanding the development of this circuitry is pivotal to fully comprehending nervous system function. The formation of these connections, or synapses, is dependent on both the genetic makeup of the cell, as well as the information it receives from sensory organs. Much evidence indicates that neuronal activity plays a critical role in the development of the circuitry in the brain. The ability of neurons to undergo physiological and morphological modifications in response to changes in their inputs has been termed plasticity. One potential mechanism underlying neuronal plasticity is the activity-dependent induction of target genes. Therefore, gene products that induce structural changes in neurons and are regulated by activity are well suited for controlling plasticity. Here I describe experiments that elucidate a mechanism by which one of these genes, Candidate Plasticity Gene 15 (CPG15) contributes to axon arborization of motor neurons and synaptogenesis at the vertebrate neuromuscular junction (NMJ). Prior in vivo studies showed that overexpression of this activity regulated membrane-bound protein induces an elaboration of dendritic arbors in Xenopus optic tectal neurons by acting in a non-cell autonomous manner, presumably by acting as a ligand. I first describe in this thesis the cloning and sequence of Xenopus laevis cpg15 and its expression pattern during development of the nervous system. Second, I describe the morphological development of motor neuron axons. Finally I provide evidence that cpg15 induces motor neuron axon growth by acting to stabilize branches as well as induce formation of branches that have synapses. These experiments not only elucidate the role of cpg15 in the peripheral nervous system, but they also allow us to interpret and understand the results of previous experiments carried out in the retinotectal system of the Xenopus tadpole. In conclusion, I use all our current knowledge of this protein to present a model that describes how this molecule contributes to the morphological development of neurons.